US3138529A - Tetracycline antibiotic compositions for oral use - Google Patents
Tetracycline antibiotic compositions for oral use Download PDFInfo
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- US3138529A US3138529A US120472A US12047261A US3138529A US 3138529 A US3138529 A US 3138529A US 120472 A US120472 A US 120472A US 12047261 A US12047261 A US 12047261A US 3138529 A US3138529 A US 3138529A
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- US
- United States
- Prior art keywords
- tetracycline
- antibiotic
- deoxytetracycline
- plus
- demethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 239000000203 mixture Substances 0.000 title claims description 21
- 229940072172 tetracycline antibiotic Drugs 0.000 title description 15
- CYIDZMCFTVVTJO-UHFFFAOYSA-N pyromellitic acid Chemical compound OC(=O)C1=CC(C(O)=O)=C(C(O)=O)C=C1C(O)=O CYIDZMCFTVVTJO-UHFFFAOYSA-N 0.000 claims description 20
- 230000003115 biocidal effect Effects 0.000 claims description 16
- SRPWOOOHEPICQU-UHFFFAOYSA-N trimellitic anhydride Chemical compound OC(=O)C1=CC=C2C(=O)OC(=O)C2=C1 SRPWOOOHEPICQU-UHFFFAOYSA-N 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 230000003389 potentiating effect Effects 0.000 claims description 5
- 150000001875 compounds Chemical class 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 24
- 239000004098 Tetracycline Substances 0.000 description 15
- 235000019364 tetracycline Nutrition 0.000 description 15
- 239000002671 adjuvant Substances 0.000 description 14
- 150000003522 tetracyclines Chemical class 0.000 description 14
- 229960002180 tetracycline Drugs 0.000 description 11
- 229930101283 tetracycline Natural products 0.000 description 11
- RMVMLZHPWMTQGK-SOUFLCLCSA-N (4s,4as,5as,6s,12ar)-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=CC=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O RMVMLZHPWMTQGK-SOUFLCLCSA-N 0.000 description 8
- GUXHBMASAHGULD-SEYHBJAFSA-N (4s,4as,5as,6s,12ar)-7-chloro-4-(dimethylamino)-1,6,10,11,12a-pentahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1([C@H]2O)=C(Cl)C=CC(O)=C1C(O)=C1[C@@H]2C[C@H]2[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]2(O)C1=O GUXHBMASAHGULD-SEYHBJAFSA-N 0.000 description 8
- 241000700159 Rattus Species 0.000 description 8
- XMEVHPAGJVLHIG-FMZCEJRJSA-N chembl454950 Chemical compound [Cl-].C1=CC=C2[C@](O)(C)[C@H]3C[C@H]4[C@H]([NH+](C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O XMEVHPAGJVLHIG-FMZCEJRJSA-N 0.000 description 8
- JCSGAUKCDAVARS-UHFFFAOYSA-N demethyltetracycline Natural products CN(C1C(=C(C(C2(C(=C3C(C4=C(C=CC=C4C(C3CC12)O)O)=O)O)O)=O)C(=O)N)O)C JCSGAUKCDAVARS-UHFFFAOYSA-N 0.000 description 8
- 229960004989 tetracycline hydrochloride Drugs 0.000 description 8
- 230000036765 blood level Effects 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 210000002966 serum Anatomy 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 239000004099 Chlortetracycline Substances 0.000 description 4
- 239000004100 Oxytetracycline Substances 0.000 description 4
- CYDMQBQPVICBEU-UHFFFAOYSA-N chlorotetracycline Natural products C1=CC(Cl)=C2C(O)(C)C3CC4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-UHFFFAOYSA-N 0.000 description 4
- 229960004475 chlortetracycline Drugs 0.000 description 4
- CYDMQBQPVICBEU-XRNKAMNCSA-N chlortetracycline Chemical compound C1=CC(Cl)=C2[C@](O)(C)[C@H]3C[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O CYDMQBQPVICBEU-XRNKAMNCSA-N 0.000 description 4
- 235000019365 chlortetracycline Nutrition 0.000 description 4
- 229960000625 oxytetracycline Drugs 0.000 description 4
- IWVCMVBTMGNXQD-PXOLEDIWSA-N oxytetracycline Chemical compound C1=CC=C2[C@](O)(C)[C@H]3[C@H](O)[C@H]4[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-PXOLEDIWSA-N 0.000 description 4
- 235000019366 oxytetracycline Nutrition 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 4
- 229940040944 tetracyclines Drugs 0.000 description 4
- -1 bromo 6 demethyl- 6-deoxytetracycline Chemical compound 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000002708 enhancing effect Effects 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 125000002346 iodo group Chemical group I* 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- ARCGXLSVLAOJQL-UHFFFAOYSA-N trimellitic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1 ARCGXLSVLAOJQL-UHFFFAOYSA-N 0.000 description 2
- ICIDIYCNVITODC-UVPAEMEASA-N (4s,4as,5ar,12ar)-2-carbamoyl-4-(dimethylazaniumyl)-10,11,12a-trihydroxy-7-nitro-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracen-1-olate Chemical compound C1C2=C([N+]([O-])=O)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O ICIDIYCNVITODC-UVPAEMEASA-N 0.000 description 1
- MTCQOMXDZUULRV-ADOAZJKMSA-N (4s,4as,5ar,12ar)-4-(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=CC=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O MTCQOMXDZUULRV-ADOAZJKMSA-N 0.000 description 1
- SWWQQSDRUYSMAR-UHFFFAOYSA-N 1-[(4-hydroxyphenyl)methyl]-1,2,3,4-tetrahydroisoquinoline-6,7-diol;hydrochloride Chemical group Cl.C1=CC(O)=CC=C1CC1C2=CC(O)=C(O)C=C2CCN1 SWWQQSDRUYSMAR-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003701 inert diluent Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
Definitions
- This invention relates to novel antibiotic compositions and more particularly is concerned with the preparation of novel antibiotic compositions containing a tetracycline antibiotic and a potentiating agent therefor whereby effective blood levels of the antibiotic are obtained more rapidly, reach a higher level and are maintained over a longer period of time than would be expected following oral administration of a tetracycline antibiotic without the potentiating agent.
- Citric acid has proven to be one of the best adjuvants for increasing the rate of absorption and for enhancing serum levels of orally administered tetracycline, in the standard experimental animal, such as, the albino rat.
- pyromellitic acid and trimellitic acid 1,2- anhydride are superior to the known adjuvants, such as citric acid, for increasing the blood levels in terms of tetracycline equivalents.
- tetracycline antibiotic as used throughout the specification and claims is intended to embrace any of the foregoing tetracycline compounds. It is to be understood that those tetracyclines which are commercial or potentially commercial drugs such as chlortetracycline, tetracycline, oxytetracycline, 6 demethylchlortetracycline and 6-demethyltetracycline are especially preferred because of their ready availability and demonstrated clinical usefulness.
- the tetracyclines may be used in the form of their free bases or in the more preferred form of administration as a salt thereof, particularly the hydrochloride salt.
- novel adjuvants may be used in the form of their free acids as illustrated or they may be used equally as well in the form of their simple salts such as the alkali metal or ammonium salts.
- the proportion of the tetracycline antibiotic to adjuvant may vary over a fairly Wide range.
- the adjuvant is preferably used in an amount ranging from about 1 to 3 parts by weight of the tetracycline antibiotic. As the adjuvant is much cheaper than the tetracycline antibiotic it is preferred to operate with an excess of adjuvant and optimum results will usually be obtained with an amount of adjuvant ranging from equal amounts to three times the Weight of the tetracycline antibiotic.
- a dosage unit form of the new compositions of this invention is most conveniently a powdered mixture of e the antibiotic and the adjuvant enclosed in a gelatin capsule.
- the dosage unit form may contain from about 25 to 500 mg. of one of the desired tetracyclines with from 1 to 3 parts by Weight of adjuvant.
- An inert diluent such as starch, sucrose, and magnesium stearate may be added if desired.
- a preferred composition consists of 250 mg. of a tetracycline antibiotic free base together with 500 to 750 mg. of adjuvant in a soft gelatin capsule. If desired, the composition may be granulated and administered as such, or may be compressed into tablets suitable for oral administration.
- a composition can be formulated into numerous pharmaceutical substances such as pediatric drops, elixirs, and various other conventional pharmaceutical forms of medication. These will be administered by the attending physician or veterinarian in accordance with the age and condition of the patient, nature of the disease and in view of the other considerations peculiar to the individual patient.
- compositions of this invention are expected to be as an orally administered tetracycline antibiotic composition for use in human therapy, it is also within the scope of the present invention to provide suspensions or dispersions of the tetracycline antibiotic compositions for use in the treatment of animals in which case aqueous solutions may be employed for intravenous administration or solutions or suspensions with organic solvents may be prepared for intramuscular administration.
- EXAMPLE 1 A group of three albino rats ranging from 175-300 grams were dosed with a solution or suspension of 50 mg./ kg. of tetracycline hydrochloride via a feeding needle. A similar group of three rats received a mixture of 50 mg./kg. of tetracycline hydrochloride plus mg./kg. of citric acid. A similar group receiveied 50 mg./kg. of tetracycline hydrochloride plus 140 mg./kg. of pyromellitic acid. A similar group received 50 mg./ kg. of tetra cycline hydrochloride plus 140 mg./kg. of trimellitic acid 1,2-anhydride. The blood levels were determined four hours after dosing. The results obtained are shown in the table below:
- EXAMPLE 2 A group of three albino rats ranging from -300 grams were closed with a solution or suspension of 50 mg./ kg. of tetracycline hydrochloride via a feeding needle. A similar group of three rats received a mixture of 50 mg./kg. of tetracycline hydrochloride plus 50 mg./kg. of citric acid. A similar group received 50 mg./kg. of tetracycline hydrochloride plus 50 mg./kg. of pyromellitic acid. A smilar group received 50 mg./ kg. of tetracycline hydrochloride plus 50 trig/kg. of trimellitic acid 1,2-anhydride. The serum levels were determined four hours after administration. The results obtained are shown in the table below:
- Tetracycline H01 50 3.78 Tetracycline H01 plus citric acid 504- 4. 77 Tetracycline 1101 plus pyromellitic acid 50+50 9. 39 Tetracycline H0] plus trimellitic acid 1,2-
- EXAMPLE 4 Groups of five albino rats ranging from 175-300 grams were dosed with a solution or suspension of 50 mg./kg. of 6-demethylchlortetracycline hydrochloride via a feeding needle. A similar group of five rats received a mixture of 50 mg./kg. of 6-demethylchlortetracycline hydrochloride plus 50 mg./kg. of citric acid. A similar group received 50 mg./kg. of 6-demethylchlortetracycline hydrochloride plus 50 mg./ kg. of pyromellitic acid. A similar group received 50 rug/kg. of 6-demethylchlortetracycline hydrochloride plus 50 mg./kg. of trimellitic acid 1,2-anhydride. The serum levels were determined four hours It will be noted that the adjuvants of this invention give much greater blood levels than does citric acid and about twice the blood levels obtained by the controls.
- composition of matter comprising a tertacycline antibiotic and from 1 to 3 parts by weight of a compound of the group consisting of pyromellitic acid and trimellitic acid 1,2-anhydride as an oral potentiating agent therefor.
- composition according to claim 1 in which the antibiotic is chlortetracycline.
- composition according to claim 1 in which the antibiotic is tetracycline.
- composition according to claim 1 in which the antibiotic is oxytetracycline.
- a method of increasing the absorption of a tetracycline antibiotic when administered orally which comprises the step of administering therewith from 1 to 3 parts by weight of a compound of the group consisting of pyromellitic acid and trimellitic acid 1,2-anhydride.
- An article of manufacture in dosage unit form suitable for oral administration comprising a mixture of from 25 to 500 milligrams of a tetracycline antibiotic and from 1 to 3 parts of a compound of the group consisting of pyromellitic acid and trimellitic acid 1,2-anhydride.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
United States Patent Ofi ice 3,138,529 Patented June 23, 1964 This invention relates to novel antibiotic compositions and more particularly is concerned with the preparation of novel antibiotic compositions containing a tetracycline antibiotic and a potentiating agent therefor whereby effective blood levels of the antibiotic are obtained more rapidly, reach a higher level and are maintained over a longer period of time than would be expected following oral administration of a tetracycline antibiotic without the potentiating agent.
The use of potentiating agents or adjuvants for the purpose of enhancing the blood levels of orally administered tetracycline antibiotics has come into widespread use in recent years. Citric acid has proven to be one of the best adjuvants for increasing the rate of absorption and for enhancing serum levels of orally administered tetracycline, in the standard experimental animal, such as, the albino rat.
In accordance with the present invention we have now discovered that pyromellitic acid and trimellitic acid 1,2- anhydride are superior to the known adjuvants, such as citric acid, for increasing the blood levels in terms of tetracycline equivalents.
The tetracycline antibiotics which may be administered orally in admixture with the novel adjuvants of this invention include the known biologically active tetracyclines, among which may be mentioned tetracycline, chlortetracycline, oxytetracycline, 6 demethylchlortetracycline, 6-demethyltetracycline, 6-deoxytetracycline, 6- demethyl-6-deoxytetracycline, 7 bromo 6 demethyl- 6-deoxytetracycline, 7 chloro 6 demethyl 6 deoxytetracycline, 7 iodo 6 demethyl 6 deoxytetracyline, 7 nitro 6 demethyl 6 deoxytetracycline, 9 nitro- 6-demethyl-6-deoxytetracycline, 7-bromo 6 deoxytetracycline, 7-iodo-6-deoxytetracycline, 9-nitro-6-deoxytetracycline, 7-nitro-6-deoxytetracycline, 7-amino-6-demethyl- :6 deoxytetracycline, 9-amino-6-demethyl-6-deoxytetracycline, 9 amino 6 deoxytetracycline, 9 amino 7- brorno 6 deoxytetracycline, 9 amino 7 nitro 6- deoxytetracycline, 7 iodo 5 hydroxy 6 deoxytetracycline, 7-bromo-5-hydroXy-6-deoxytetracycline, S-hydroxy-6-deoxytetracycline, 9-amino-7-bromo-6-demethyl- 6-deoxytetracycline, 7-bromo-9-nitro-6-demethyl-6-deoxytetracycline, 9-amino-7-chloro-6-demethyl 6 deoxytetracycline, 7-chloro-9-nitro-6-demethyl-6-deoxytetracycline, etc.
The expression tetracycline antibiotic as used throughout the specification and claims is intended to embrace any of the foregoing tetracycline compounds. It is to be understood that those tetracyclines which are commercial or potentially commercial drugs such as chlortetracycline, tetracycline, oxytetracycline, 6 demethylchlortetracycline and 6-demethyltetracycline are especially preferred because of their ready availability and demonstrated clinical usefulness.
The tetracyclines may be used in the form of their free bases or in the more preferred form of administration as a salt thereof, particularly the hydrochloride salt.
The novel adjuvants may be used in the form of their free acids as illustrated or they may be used equally as well in the form of their simple salts such as the alkali metal or ammonium salts.
The proportion of the tetracycline antibiotic to adjuvant may vary over a fairly Wide range. The adjuvant is preferably used in an amount ranging from about 1 to 3 parts by weight of the tetracycline antibiotic. As the adjuvant is much cheaper than the tetracycline antibiotic it is preferred to operate with an excess of adjuvant and optimum results will usually be obtained with an amount of adjuvant ranging from equal amounts to three times the Weight of the tetracycline antibiotic.
A dosage unit form of the new compositions of this invention is most conveniently a powdered mixture of e the antibiotic and the adjuvant enclosed in a gelatin capsule. The dosage unit form may contain from about 25 to 500 mg. of one of the desired tetracyclines with from 1 to 3 parts by Weight of adjuvant. An inert diluent such as starch, sucrose, and magnesium stearate may be added if desired. A preferred composition consists of 250 mg. of a tetracycline antibiotic free base together with 500 to 750 mg. of adjuvant in a soft gelatin capsule. If desired, the composition may be granulated and administered as such, or may be compressed into tablets suitable for oral administration. Also, if desired, a composition can be formulated into numerous pharmaceutical substances such as pediatric drops, elixirs, and various other conventional pharmaceutical forms of medication. These will be administered by the attending physician or veterinarian in accordance with the age and condition of the patient, nature of the disease and in view of the other considerations peculiar to the individual patient.
As a consequence to evidence obtained from the standard experimental animal, that is, the albino rat, the principal utility of the compositions of this invention is expected to be as an orally administered tetracycline antibiotic composition for use in human therapy, it is also within the scope of the present invention to provide suspensions or dispersions of the tetracycline antibiotic compositions for use in the treatment of animals in which case aqueous solutions may be employed for intravenous administration or solutions or suspensions with organic solvents may be prepared for intramuscular administration.
The following examples are provided for illustrative purposes and may include particular features of the invention. However, the examples should not be construed as limiting the invention, many variations of which are possible without departing from the spirit or scope thereof.
EXAMPLE 1 A group of three albino rats ranging from 175-300 grams were dosed with a solution or suspension of 50 mg./ kg. of tetracycline hydrochloride via a feeding needle. A similar group of three rats received a mixture of 50 mg./kg. of tetracycline hydrochloride plus mg./kg. of citric acid. A similar group recevied 50 mg./kg. of tetracycline hydrochloride plus 140 mg./kg. of pyromellitic acid. A similar group received 50 mg./ kg. of tetra cycline hydrochloride plus 140 mg./kg. of trimellitic acid 1,2-anhydride. The blood levels were determined four hours after dosing. The results obtained are shown in the table below:
EXAMPLE 2 A group of three albino rats ranging from -300 grams were closed with a solution or suspension of 50 mg./ kg. of tetracycline hydrochloride via a feeding needle. A similar group of three rats received a mixture of 50 mg./kg. of tetracycline hydrochloride plus 50 mg./kg. of citric acid. A similar group received 50 mg./kg. of tetracycline hydrochloride plus 50 mg./kg. of pyromellitic acid. A smilar group received 50 mg./ kg. of tetracycline hydrochloride plus 50 trig/kg. of trimellitic acid 1,2-anhydride. The serum levels were determined four hours after administration. The results obtained are shown in the table below:
Table 2 Dose, Serum Substance mg./kg. Levels meg/ml.
Tetracycline H01 50 3.78 Tetracycline H01 plus citric acid 504- 4. 77 Tetracycline 1101 plus pyromellitic acid 50+50 9. 39 Tetracycline H0] plus trimellitic acid 1,2-
anhydridc 50+50 6.61
EXAMPLE 3 T able 3 Dose, Serum Substance rug/kg. Levels,
meg/1n].
Demethyltetracycline H01 50 2. 80 Demethyltetracycline 1101 plus citric acid 50-1-50 4.40 Demethyltetracycline H01 plus pyromellitic acid 50-1-50 7. 24 Demethyltetracycline H01 plus trimellitic acid 1,2-anhydride 504-50 5. 21
EXAMPLE 4 Groups of five albino rats ranging from 175-300 grams were dosed with a solution or suspension of 50 mg./kg. of 6-demethylchlortetracycline hydrochloride via a feeding needle. A similar group of five rats received a mixture of 50 mg./kg. of 6-demethylchlortetracycline hydrochloride plus 50 mg./kg. of citric acid. A similar group received 50 mg./kg. of 6-demethylchlortetracycline hydrochloride plus 50 mg./ kg. of pyromellitic acid. A similar group received 50 rug/kg. of 6-demethylchlortetracycline hydrochloride plus 50 mg./kg. of trimellitic acid 1,2-anhydride. The serum levels were determined four hours It will be noted that the adjuvants of this invention give much greater blood levels than does citric acid and about twice the blood levels obtained by the controls.
We claim:
1. A composition of matter comprising a tertacycline antibiotic and from 1 to 3 parts by weight of a compound of the group consisting of pyromellitic acid and trimellitic acid 1,2-anhydride as an oral potentiating agent therefor.
2. A composition according to claim 1 in which the antibiotic is chlortetracycline.
3. A composition according to claim 1 in which the antibiotic is tetracycline.
4. A composition according to claim 1 in which the antibiotic is oxytetracycline.
5. A composition according to claim 1 in which the antibiotic is 6-demethylchlortetracycline.
6. A comprosition according to claim 1 in which the antibiotic is 6-demethyltetracycline.
7. A method of increasing the absorption of a tetracycline antibiotic when administered orally which comprises the step of administering therewith from 1 to 3 parts by weight of a compound of the group consisting of pyromellitic acid and trimellitic acid 1,2-anhydride.
8. A method according to claim 7 in which the antibiotic is chlortetracycline.
9. A method according to claim 7 in which the antibiotic is tetracycline.
10. A method according to claim 7 in which the antibiotic is oxytetracycline.
11. A method according to claim 7 in which the antibiotic is 6-demethylchlortetracycline.
12. A method according to claim 7 in which the antibiotic is 6-demethyltetracycline.
13. An article of manufacture in dosage unit form suitable for oral administration comprising a mixture of from 25 to 500 milligrams of a tetracycline antibiotic and from 1 to 3 parts of a compound of the group consisting of pyromellitic acid and trimellitic acid 1,2-anhydride.
References Cited in the file of this patent UNITED STATES PATENTS Wirth Sept. 29, 1959 OTHER REFERENCES
Claims (1)
1. A COMPOSITION OF MATTER COMPRISING A TERTACYLINE ANTIBIOTIC AND FROM 1 TO 3 PARTS BY WEIGHT OF A COMPOUND OF THE GROUP CONSISTING OF PYROMELLITIC ACID AND TRIMELLITIC ACID 1,2-ANHYDRIDE AS AN ORAL POTENTIATING AGENT THEREFOR.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US120472A US3138529A (en) | 1961-06-29 | 1961-06-29 | Tetracycline antibiotic compositions for oral use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US120472A US3138529A (en) | 1961-06-29 | 1961-06-29 | Tetracycline antibiotic compositions for oral use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3138529A true US3138529A (en) | 1964-06-23 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US120472A Expired - Lifetime US3138529A (en) | 1961-06-29 | 1961-06-29 | Tetracycline antibiotic compositions for oral use |
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| Country | Link |
|---|---|
| US (1) | US3138529A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3299124A (en) * | 1963-01-30 | 1967-01-17 | Soc Ind Fab Antibiotiques Sifa | Tetracycline cyclohexyl sulphamate and process for preparation |
| US3313701A (en) * | 1963-08-27 | 1967-04-11 | Upjohn Co | Testosterone composition of matter and process |
| US3459854A (en) * | 1964-01-13 | 1969-08-05 | Fabricationdes Antibiotiques S | Tetracycline cyclohexyl sulphamate and process for preparation |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2906666A (en) * | 1957-07-05 | 1959-09-29 | Frank E Jonas | Therapeutic mellitic acid compositions |
-
1961
- 1961-06-29 US US120472A patent/US3138529A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2906666A (en) * | 1957-07-05 | 1959-09-29 | Frank E Jonas | Therapeutic mellitic acid compositions |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3299124A (en) * | 1963-01-30 | 1967-01-17 | Soc Ind Fab Antibiotiques Sifa | Tetracycline cyclohexyl sulphamate and process for preparation |
| US3313701A (en) * | 1963-08-27 | 1967-04-11 | Upjohn Co | Testosterone composition of matter and process |
| US3459854A (en) * | 1964-01-13 | 1969-08-05 | Fabricationdes Antibiotiques S | Tetracycline cyclohexyl sulphamate and process for preparation |
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